Figure - available via license: Creative Commons Attribution 4.0 International
Content may be subject to copyright.
A. Antibodies against hillock of the neurons of rat cerebellum. Immunohistochemistry on rat sagittal cerebellum sections. Note the strong atypical reactivity of a PCD SCLC serum against the hillock axon of the neurons, mainly in Purkinje cells. Nuclei are counterstained with hematoxilin. B. Immunofluorescence on live hippocampal neurons. Hippocampal neurons incubated with CSF 1/5 diluted of a PCD SCLC patient. Reactivity of the patient against the membrane of the neuron is seen in green and MAP2 staining in red to ensure the neuronal lineage. Nuclei are seen blue with DAPI. (objective 100x oil)
Source publication
The goal of this study is to determine whether patients with paraneoplastic cerebellar degeneration (PCD) and small-cell lung cancer (SCLC) have a specific repertoire of antibodies, if SOX1 antibodies (SOX1-ab) can predict the presence of SCLC, and if antibodies to cell surface antigens occur in this syndrome. Antibody analysis was done using immun...
Citations
... Neural antibody specificity [3,4,36]. The lower representation of SOX1-IgG might be related to the detection method used. ...
... The lower representation of SOX1-IgG might be related to the detection method used. In the current study, an antigenspecific test was performed only if a SOX1-IgG compatible staining was noted in the indirect immunofluorescence assay on mouse tissue, whereas in previous studies, screening was performed upfront with an antigen-specific test [3,36]. Despite these differences, the neural autoantibody profiles are overall similar to those recognized with SCLC, such as ANNA-1, ANNA-3/DACH-1, GABA B R-IgG and P/Q-type VGCC-IgG, and reflect the tumor's onconeural antigen expression [3]. ...
Background and purpose
Paraneoplastic neurological autoimmunity is well described with small‐cell lung cancer, but information is limited for other neuroendocrine neoplasms (NENs).
Methods
Adult patients with histopathologically confirmed non‐pulmonary NENs, neurological autoimmunity within 5 years of NEN diagnosis, and neural antibody testing performed at the Mayo Clinic Neuroimmunology Laboratory (January 2008 to March 2023) were retrospectively identified. Control sera were available from patients with NENs without neurological autoimmunity (116).
Results
Thirty‐four patients were identified (median age 68 years, range 31–87). The most common primary tumor sites were pancreas (nine), skin (Merkel cell, eight), small bowel/duodenum (seven), and unknown (seven). Five patients received immune checkpoint inhibitor (ICI) therapy before symptom onset; symptoms preceded cancer diagnosis in 62.1% of non‐ICI‐treated patients. The most frequent neurological phenotypes (non‐ICI‐treated) were movement disorders (12; cerebellar ataxia in 10), dysautonomia (six), peripheral neuropathy (eight), encephalitis (four), and neuromuscular junction disorders (four). Neural antibodies were detected in 55.9% of patients studied (most common specificities: P/Q‐type voltage‐gated calcium channel [seven], muscle‐type acetylcholine receptor [three], anti‐neuronal nuclear antibody type 1 [three], and neuronal intermediate filaments [two]), but in only 6.9% of controls. Amongst patients receiving cancer or immunosuppressive therapy, 51.6% had partial or complete recovery. Outcomes were unfavorable in 48.3% (non‐ICI‐treated) and neural autoantibody positivity was associated with poor neurological outcome.
Discussion
Neurological autoimmunity associated with non‐pulmonary NENs is often multifocal and can be treatment responsive, underscoring the importance of rapid recognition and early treatment.
... Among PNS cases, the proportion of PCD patients who are positive for anti-SOX1 and anti-VGCC antibodies is reported to be 18.2% (20/110) (7) and 3.8% (9/236) (8), respectively. Anti-SOX1 antibody is a predictor of SCLC in cerebellar ataxic patients, with a specificity of 100% and a sensitivity of 49% (9). However, only 1.9% of PCD cases (4/103) are positive for both anti-GAD65 and anti-SOX1 antibodies (7). ...
Paraneoplastic cerebellar degeneration (PCD) is a paraneoplastic neurological syndrome that is rarely accompanied by seropositivity with a combination of multiple antibodies. We herein report a 50-year-old man with PCD accompanied by small-cell lung cancer (SCLC). This patient was seropositive for anti-glutamic acid decarboxylase 65, anti-SRY-related HMG-box gene 1 and anti-voltage-gated calcium channel antibodies. After chemoradiation therapy without immunotherapy, cerebellar ataxia of the trunk and limbs markedly improved, along with a notable amelioration of SCLC. This case suggests that tumor therapy should be started immediately and that a panel of anti-neuronal antibodies should be evaluated when PCD with SCLC is suspected.
... Using this alternative approach the number of cases that need CBA is reduced to 26% but at the expense to miss a few CBA positive cases (3% or 1/34 in this series) ( Figure 3). The current findings also confirmed our earlier observation that SOX1-abs detected by CBA tightly associate with the presence of PNS and SCLC (1,7,8). A recent study suggested that SOX1-abs should be confirmed by 3 assays (line blot, TBA, and CBA) or at least TBA plus either line blot or CBA to support the diagnosis of PNS (9). ...
SOX1 antibodies (SOX1-abs) are associated with paraneoplastic neurological syndromes (PNS) and small cell lung cancer (SCLC). In many clinical laboratories SOX1-abs are determined by commercial line blots without confirmation by cell-based assay (CBA) with HEK293 cells expressing SOX1. However, the diagnostic yield of commercial line blots is low and the accessibility to the CBA, that is not commercially available, limited. Here, we evaluated if the addition of the band intensity data of the line blot and the immunoreactivity in a tissue-based assay (TBA) improve the diagnostic performance of the line blot. We examined serum of 34 consecutive patients with adequate clinical information that tested positive for SOX1-abs in a commercial line blot. Samples were also assessed by TBA and CBA. SOX1-abs were confirmed by CBA in 17 (50%) patients, all (100%) had lung cancer (SCLC in 16) and 15/17 (88%) had a PNS. In the remaining 17 patients the CBA was negative and none had PNS associated with lung cancer. TBA was assessable in 30/34 patients and SOX1-abs reactivity was detected in 15/17 (88%) with positive and in 0/13 (0%) with negative CBA. Only 2 (13%) of the 15 TBA-negative patients were CBA-positive. The frequency of TBA-negative but CBA-positive increased from 10% (1/10) when the band intensity of the line blot was weak to 20% (1/5) in patients with a moderate or strong intensity band. Confirmation by CBA should be mandatory for samples (56% in this series) not assessable (4/34; 12%) or negative in the TBA (15/34; 44%).
... These antibodies were initially called anti-glial nuclear antibodies (AGNA), but later confirmed to target SOX1 protein [4]. High specificity for lung cancer diagnosis was observed, as well as an association with paraneoplastic Lambert-Eaton myasthenic syndrome (LEMS) and cerebellar ataxia [3][4][5][6]. ...
... The aims of the present study were to characterize the relevant clinical correlates of SOX1-Abs and to determine the most accurate diagnostic methods to meaningfully detect them. First, we identified LEMS and rapidly progressive cerebellar syndrome (sometimes combined) as the most common clinical phenotypes associated with SOX1-Abs within the definite PNS group, which is in line with previous reports [3][4][5][6]12]. Moreover, we described novel associations with other high-risk clinical phenotypes and isolated SOX1-positivity, including limbic encephalitis, encephalomyelitis and gastrointestinal pseudo-obstruction; these and other additional presentations have previously been observed mostly in patients with co-occurrent Hu antibodies [4,9]. ...
... Importantly, SCLC is considered very immunogenic and, due to its neuroectodermal origin and dedifferentiation, often expresses multipotent cell markers like SOX group B family proteins [13]. Furthermore, SOX1-Abs have been reported in up to 20-30% of patients with SCLC without PNS [4,5], whereas no anti-SOX1 positivity was found in a large cohort of nonneurological patients with other types of cancer nor in another series of patients with paraneoplastic cerebellar ataxia and tumors different from SCLC [3,6]. Then, we retest the available samples to establish what laboratory test or combination of tests was the most accurate to detect clinically relevant SOX1-Abs. ...
Objective
To describe the clinical associations of SOX1 antibodies (SOX1-Abs), determine the accuracy of various detection techniques, and propose laboratory criteria to identify definite paraneoplastic neurological syndromes (PNS) associated with SOX1-Abs.
Methods
Single-center, retrospective study of patients referred to the French Reference Center between 2009 and 2019 for confirmation of SOX1-Ab positivity, without concurrent neural antibodies. Patients were classified according to the updated diagnostic PNS criteria; biological samples were systematically retested with three distinct techniques (line blot, cell-based assay, indirect immunofluorescence).
Results
Among 77 patients with isolated SOX1-Ab positivity, 23 (29.9%) fulfilled the criteria for definite PNS; all of them had lung cancer (mostly small-cell) and presented mainly with Lambert-Eaton myasthenic syndrome (10/23) and rapidly progressive cerebellar ataxia (6/23). SOX1-Ab positivity varied depending on the laboratory methods which were used, and a single technique was not sufficient to draw conclusions about the PNS diagnosis. The combination of an antigen-specific test (line blot and/or cell-based assay) and immunofluorescence showed the highest accuracy (81.5%, 95% CI 70.0–90.1) in identifying definite PNS. Moreover, when the PNS-Care score was recalculated assigning three points at the laboratory-level only to patients with positive “antigenic-specific test + immunofluorescence” and 0 points to the remaining cases, a higher certainty for definite and non-PNS was achieved (from 41/77, 53.2%, to 60/77, 77.9%; p < 0.001).
Conclusion
SOX1-Abs should be considered high-risk antibodies only when detected with a positive antigenic-specific test and immunofluorescence. Other laboratory results and clinical associations different from Lambert-Eaton myasthenic syndrome and rapidly progressive cerebellar ataxia should be carefully reassessed to rule out false positivity and alternative diagnoses.
... A good example of how antibodies conception may evolve is represented by Zic4 antibodies, which were initially reported in the serum of patients with PCA and smallcell lung cancer (SCLC) [135]. However, posterior studies indicated that they might simply be biomarkers of SCLC rather than of PNS [136,137]. Likewise, serum glutamate receptor δ2 (GluRδ2) antibodies were claimed to occur in opsoclonus-myoclonus syndrome [138], a disease related to cerebellar ataxia that has long been difficult to characterize immunologically, being generally not associated with neural antibodies [139,140]. ...
Major advances in our knowledge concerning autoimmune and paraneoplastic cerebellar ataxias have occurred in the last 20 years. The discovery of several neural antibodies represents an undeniable contribution to this field, especially those serving as good biomarkers of paraneoplastic neurological syndromes and those showing direct pathogenic effects. Yet, many patients still lack detectable or known antibodies, and also many antibodies have only been reported in few patients, which makes it difficult to define in detail their clinical value. Nevertheless, a notable progress has additionally been made in the clinical characterization of patients with the main neural antibodies, which, although typically present with a subacute pancerebellar syndrome, may also show either hyperacute or chronic onsets that complicate the differential diagnoses. However, prodromal and transient features could be useful clues for an early recognition, and extracerebellar involvement may also be highly indicative of the associated antibody. Moreover, important advances in our understanding of the pathogenesis of cerebellar ataxias include the description of antibody effects, especially those targeting cell-surface antigens, and first attempts to isolate antigen-specific T-cells. Furthermore, genetic predisposition seems relevant, although differently involved according to cancer association, with particular HLA observed in non-paraneoplastic cases and genetic abnormalities in the tumor cells in paraneoplastic ones. Finally, immune checkpoint inhibitors used as cancer immunotherapy may rarely induce cerebellar ataxias, but even this undesirable effect may in turn serve to shed some light on their physiopathology. Herein, we review the principal novelties of the last 20 years regarding autoimmune and paraneoplastic cerebellar ataxias.
... [10][11][12] P/Q-type voltage-gated calcium channel (P/Q-VGCC) antibodies are prevalent in about 40% of patients with PCD with small-cell lung cancer. 13,14 The antibodies are commonly associated with Lambert-Eaton myasthenic syndrome (LEMS) and may additionally present with PCD (with or without LEMS), possibly due to the recognition of varying target epitopes. 3,13,15 At the neuromuscular junction, P/Q-VGCC antibodies were shown to cause a downregulation and blocking of Ca v 2.1 receptors. ...
Background and Objectives Paraneoplastic cerebellar degeneration (PCD) is characterized by a widespread loss of Purkinje cells (PCs) and may be associated with autoantibodies against intracellular antigens such as Yo or cell surface neuronal antigens such as the P/Q-type voltage-gated calcium channel (P/Q-VGCC). Although the intracellular location of the target antigen in anti–Yo-PCD supports a T cell–mediated pathology, the immune mechanisms in anti–P/Q-VGCC-PCD remain unclear. In this study, we compare neuropathologic characteristics of PCD with anti–P/Q-VGCC and anti-Yo autoantibodies in an archival autopsy cohort.
Methods We performed neuropathology, immunohistochemistry, and multiplex immunofluorescence on formalin-fixed and paraffin-embedded brain tissue of 1 anti–P/Q-VGCC, 2 anti–Yo-PCD autopsy cases and controls.
Results Anti–Yo-PCD revealed a diffuse and widespread PC loss together with microglial nodules with pSTAT1+ and CD8+granzymeB+ T cells and neuronal upregulation of major histocompatibility complex (MHC) Class I molecules. Some neurons showed a cytoplasmic immunoglobulin G (IgG) staining. In contrast, PC loss in anti–P/Q-VGCC-PCD was focal and predominantly affected the upper vermis, whereas caudal regions and lateral hemispheres were spared. Inflammation was characterized by scattered CD8+ T cells, single CD20+/CD79a+ B/plasma cells, and an IgG staining of the neuropil in the molecular layer of the cerebellar cortex and neuronal cytoplasms. No complement deposition or MHC-I upregulation was detected. Moreover, synaptophysin was reduced, and neuronal P/Q-VGCC was downregulated. In affected areas, axonal spheroids and the accumulation of amyloid precursor protein and glucose-regulated protein 78 in PCs indicate endoplasmatic reticulum stress and impairment of axonal transport. In both PCD types, calbindin expression was reduced or lost in the remaining PCs.
Discussion Anti–Yo-PCD showed characteristic features of a T cell–mediated pathology, whereas this was not observed in 1 case of anti–P/Q-VGCC-PCD. Our findings support a pathogenic role of anti–P/Q-VGCC autoantibodies in causing neuronal dysfunction, probably due to altered synaptic transmission resulting in calcium dysregulation and subsequent PC death. Because disease progression may lead to irreversible PC loss, anti–P/Q-VGCC-PCD patients could benefit from early oncologic and immunologic therapies.
... Anti-SOX1 is associated with small-cell lung cancer and is rarely accompanied by anti-GAD [7][8][9][10][11][12]. Diagnosis of SPS employs the Dalakas' criteria of well-characterized clinical manifestations, electromyography (EMG) findings, and positive serology for typical autoantibodies (Table 1). ...
Stiff Person Syndrome (SPS) is an extremely rare neurological condition characterized by muscle stiffness and painful muscle spasms. The symptoms often progress slowly and can cause disability. Antibodies to glutamic acid decarboxylase (anti-GAD) have been reported in up to 80% of the classic type of SPS. Paraneoplastic syndrome comprises 5% of SPS cases. These patients present with different malignancies including lung, thymus, breast, colon, and lymph nodes. In this paper, we report a case of a 25-year-old Vietnamese female patient with SPS presenting with unusual clinical manifestations of sudden onset, rapidly progressive spinal, abdominal, and lower limb rigidity accompanied by painful spasms, autonomic disorders, and severe, multiple bone fractures. Serologic tests detected high-titer anti-GAD, combined with anti-SOX1 antibodies, suggesting paraneoplastic SPS. Intravenous immunoglobulin has been employed as the main treatment therapy, and the patient has had a complete remission.
... The main role of Nabs is to help determine whether a neurologic syndrome could be paraneoplastic and to predict the presence of specific tumors, whose frequency and type differ according to the autoantibody identified. On the other hand, some Nabs, such as SOX1 and Hu antibodies, can be found in up to 16% of patients with small cell lung cancer (SCLC) even in the absence of a paraneoplastic syndrome [16][17][18][19]. This is important, as the detection of Nabs in patients with an overt cancer does not necessarily imply that a co-occurring neurological syndrome is paraneoplastic, especially if the clinical phenotype is not "classical" for PNS. ...
Purpose of Review
Paraneoplastic neurological syndromes (PNS) are caused by nervous system-targeting aberrant anti-tumoral immune responses. We review the updated criteria for PNS diagnosis, incorporating novel information on clinical phenotypes, neuronal autoantibodies (Nabs), and tumors. The impact of the oncologic use of immune checkpoint inhibitors (ICI) on PNS occurrence is also addressed.
Recent Findings
Clinical phenotypes and Nabs are redefined as “high/intermediate/low” risk, following the frequency of cancer association. Nabs, the diagnostic hallmark of PNS, can target intracellular or surface neuronal proteins, with important prognostic and pathogenic implications. Many novel assays have been incorporated into laboratory diagnostics, that is becoming increasingly complex. ICI fight tumors, but favor autoimmunity, thus increasing the incidence of PNS-like disorders.
Summary
Overcoming the old PNS criteria, the new ones are centered around the presence of tumor. Clinical presentation, Nabs, and tumor findings are translated in diagnostic scores, providing a useful tool for PNS diagnosis and management.
... However, psychiatric "extra-cerebellar" manifestations have been described [20]. Similarly, anti-Zic4 Abs are rare Abs that target an intracellular antigen and associate with underlying tumors and brain stem or cerebellar syndromes [21]. A false positive signal in the line blot cannot be excluded for anti-Yo and anti-Zic4 Ab findings. ...
Autoimmune encephalitis (AE) can rarely manifest as a predominantly psychiatric syndrome without overt neurological symptoms. This study’s aim was to characterize psychiatric patients with AE; therefore, anonymized data on patients with suspected AE with predominantly or isolated psychiatric syndromes were retrospectively collected. Patients with readily detectable neurological symptoms suggestive of AE (e.g., epileptic seizures) were excluded. Patients were classified as “probable psychiatric AE (pAE),” if well-characterized neuronal IgG autoantibodies were detected or “possible pAE” (e.g., with detection of nonclassical neuronal autoantibodies or compatible cerebrospinal fluid (CSF) changes). Of the 91 patients included, 21 (23%) fulfilled our criteria for probable (autoantibody-defined) pAE and 70 (77%) those for possible pAE. Among patients with probable pAE, 90% had anti-NMDA receptor (NMDA-R) autoantibodies. Overall, most patients suffered from paranoid-hallucinatory syndromes (53%). Patients with probable pAE suffered more often from disorientation ( p < 0.001) and impaired memory ( p = 0.001) than patients with possible pAE. Immunotherapies were performed in 69% of all cases, mostly with high-dose corticosteroids. Altogether, 93% of the patients with probable pAE and 80% of patients with possible pAE reportedly benefited from immunotherapies ( p = 0.251). In summary, this explorative, cross-sectional evaluation confirms that autoantibody-associated AE syndromes can predominantly manifest as psychiatric syndromes, especially in anti-NMDA-R encephalitis. However, in three out of four patients, diagnosis of possible pAE was based on nonspecific findings (e.g., slight CSF pleocytosis), and well-characterized neuronal autoantibodies were absent. As such, the spectrum of psychiatric syndromes potentially responding to immunotherapies seems not to be limited to currently known autoantibody-associated AE. Further trials are needed.
... The immune-related myelitis was probably triggered by immunotherapy and not by tumor progression. A descriptive study showed that the exacerbation or appearance of a PNS can be associated with an effective tumor response soon after the initiation of immunotherapy [20]. The results were as same as our results. ...
Paraneoplastic neurologic syndromes(PNSs) caused by immune checkpoint inhibitors(ICIs) is rare and requires clinicians to differentiate between disease progression and immune-related adverse effects(irAEs). We hereby report the case of immune-related myelitis accompanied by positive paraneoplastic autoantibodies following durvalumab treatment for extensive-stage small cell lung cancer (ES-SCLC). A 70-year-old Chinese woman with ES-SCLC was administered durvalumab with etoposid-platinum(EP) as first-line treatment. Four cycles after treatment with EP plus ICI, she developed immune-related myelitis with positive paraneoplastic autoantibodies (CV2, SOX1, ZIC4). Spinal MRI showed diffuse abnormal signal shadow in the cervicothoracic spinal cord. She was discontinued for chemotherapy, and treated with high-dose steroids, intravenous immunoglobulin and plasmapheresis, maintenance therapy with steroids resulted in a favorable neurologic outcome. This is the first report of durvalumab-related PNSs. We supposed that the development of paraneoplastic myelitis was causally related to immune activation by durvalumab. Prompt diagnosis and therapeutic intervention are essential for the effective treatment of paraneoplastic myelitis.
